Papers by John Dalrymple-alford
Movement Disorders Clinical Practice, Feb 18, 2021
Objective To examine the relationship between neuropsychiatric symptoms burden and disability in ... more Objective To examine the relationship between neuropsychiatric symptoms burden and disability in cognitively impaired older Latinos. Methods Subjects in the cross-sectional study were 95 cognitively impaired (both demented and non-demented) non-institutionalized Latino elderly participating in an epidemiological cohort study and their family caregivers. Care recipient neuropsychiatric symptoms (Neuropsychiatric Inventory) and level of functional impairment (i.e. impairment in activities of daily living and instrumental activities of daily living) were assessed through interviews with family caregivers. Results Both NPI total score and NPI depression subscale score were significantly associated with disability before and after controlling for potential confounding variables. The strength of the association between higher neuropsychiatric symptom levels and higher disability was similar for both the cognitively impaired not demented and demented groups. Conclusions Neuropsychiatric symptoms are associated with increased disability in a community sample of cognitively impaired Latino elderly. More effective identification and treatment of neuropsychiatric symptoms may improve functioning in older Latinos and reduce health disparities for this population.
European Journal of Neuroscience, Sep 1, 2005
Background: People with Parkinson's disease who meet criteria for mild cognitive impairment are a... more Background: People with Parkinson's disease who meet criteria for mild cognitive impairment are at increased risk of dementia. It is not known which tests are more effective than others for identifying the risk of dementia. Methods: At baseline, we assessed performance on 21 neuropsychological test measures spanning five cognitive domains in a prospective longitudinal study of 196 non-demented people with Parkinson's. Elastic net logistic regression was used to identify a pair of tests from each cognitive domain that best predicted conversion to dementia over a four year period. The optimal tests most predictive of dementia were also determined when mild cognitive impairment was derived from a logistic-regression classifier that used all 21 measures simultaneously. Results: With two tests per domain, the resulting mild cognitive impairment group (N=87/196) captured 44 of 51 individuals who converted to PDD; the out-of-sample relative risk of PDD was 8.0 (95% CI [4.3, 24]), similar to that achieved with the full battery (N=102/196, capturing 45/51, relative risk = 6.9). When selecting tests regardless of domain, there was strong evidence for three tests: Trail Making part B (Executive), Map Search (Attention), and CVLT-II word list acquisition (Episodic Memory). The logistic-regression classifier achieved an out-of-sample AUC of 0.90 [0.84, 0.96] and a relative risk of 12 [6, 39]. Conclusions: An abbreviated selection of neuropsychological tests can identify non-demented patients who have a high relative risk of progression to PDD.
Journal of The Royal Society of New Zealand, Aug 14, 2022
Computers & Electrical Engineering, 2021
Accurate segmentation of substantia nigra (SN) and red nucleus (RN) is challenging, yet important... more Accurate segmentation of substantia nigra (SN) and red nucleus (RN) is challenging, yet important for understanding health problems like Parkinson's disease (PD). This paper proposes an algorithm to segment SN and RN from quantitative susceptibility mapping (QSM) MRI and use the results to investigate PD. Algorithm-derived segments (based on level set and watershed transform) are compared to expert manually-derived segmentations in 40 participants. Using Bayesian regression models, we compare QSM values between PD and control groups, and investigate relationships with global cognitive ability and motor severity in PD. The proposed algorithm produces high quality segmentations, validated against expert manual segmentation. We show moderate evidence of increased QSM values in SN in PD relative to controls, with moderate evidence for association between QSM, global cognitive ability, and motor impairment in the SN in PD. We suggest an improved midbrain segmentation algorithm may be useful for monitoring iron-related disease severity in Parkinson's.
PD: A neurodegenerative movement disease. Prevalence: Affects up to 2% of individuals over 60. Ri... more PD: A neurodegenerative movement disease. Prevalence: Affects up to 2% of individuals over 60. Risk factors: Age. Diagnosis: Clinical & neuropsychological assessment Symptoms: Motor: tremor, slow movement, rigidity; Cognitive: impairments in multiple domains, including attention, executive, function, and memory; Others: sleep disturbance and swallowing difficulties. Treatment: Medications & Surgical (motor symptoms only). Regional cortical thinning is associated with cognitive status in Parkinson’s disease Mustafa M Almuqbel1,2, Tracy R Melzer1,2,3, Daniel J Myall2, Michael R MacAskill1,2, Leslie Livingston1,2, KylaLouise Horne2,4, Toni L Pitcher1,2, Ross J Keenan2,5, John C Dalrymple-Alford1,2,3,4 and Tim J Anderson1,2,3,6 1Department of Medicine, University of Otago, Christchurch, New Zealand; 2New Zealand Brain Research Institute, Christchurch, New Zealand; 3Brain Research NZ (Rangahau Roro Aotearoa), New Zealand; 4Department of Psychology, University of Canterbury, New Zealand; ...
Scientific Reports, 2021
Cerebral blood flow (CBF) measured with arterial spin labelling (ASL) magnetic resonance imaging ... more Cerebral blood flow (CBF) measured with arterial spin labelling (ASL) magnetic resonance imaging (MRI) reflects cerebral perfusion, related to metabolism, and arterial transit time (ATT), related to vascular health. Our aim was to investigate the spatial coefficient of variation (sCoV) of CBF maps as a surrogate for ATT, in volunteers meeting criteria for subjective cognitive decline (SCD), amnestic mild cognitive impairment (MCI) and probable Alzheimer’s dementia (AD). Whole-brain pseudo continuous ASL MRI was performed at 3 T in 122 participants (controls = 20, SCD = 44, MCI = 45 and AD = 13) across three sites in New Zealand. From CBF maps that included all grey matter, sCoV progressively increased across each group with increased cognitive deficit. A similar overall trend was found when examining sCoV solely in the temporal lobe. We conclude that sCoV, a simple to compute imaging metric derived from ASL MRI, is sensitive to varying degrees of cognitive changes and supports the v...
Hippocampus, 2018
Dear Editor, We thank Vann and Nelson (2018) for providing the opportunity for further discussion... more Dear Editor, We thank Vann and Nelson (2018) for providing the opportunity for further discussion on our paper, “Anterior thalamic nuclei (ATN) lesions have a greater impact than mammillothalamic tract (MTT) lesions on the extended hippocampal system”, by Perry, Mercer, Barnett, Lee and Dalrymple-Alford (2018). We contend that our findings addressed important unexplored questions concerning the effects of ATN lesions and MTT lesions. Their key point was to suggest that we have replicated previous findings on ATN and MTT lesion effects in the water-maze and radial arm maze. However, relatively few studies have examined discrete MTT lesions and there have been inconsistent findings. Our withinstudy comparison of ATN and MTT lesions obviates procedural differences between independent studies that may underpin their different findings. For example, one study examined the effects of MTT lesions on two spatial memory tasks in the water-maze and reported the opposite of what might be expec...
BackgroundPrevious research has shown an association between thalamus and cognition in Parkinson’... more BackgroundPrevious research has shown an association between thalamus and cognition in Parkinson’s disease (PD).ObjectivesTo investigate the microstructural integrity of the nuclei of the thalamus and relationship with cognition.MethodsLevel II Movement Disorder Society Task Force Criteria characterised patients with Parkinson’s disease as cognitively normal (PDN, n=51); with mild cognitive impairment (PD-MCI, n=16) or with dementia (PDD, n=15). Twenty-three healthy control subjects were included for comparison. A k-means clustering approach segmented the thalamus into regions representing nine major nuclei. Volume, fractional anisotropy and mean diffusivity of nuclei were compared between cognitive groups and the relationship with cognitive domain z-scores investigated using hierarchical Bayesian regression models.ResultsThere was an overall progressive increase in mean diffusivity as cognition deteriorated (PDN: 1.4 µm2/s (95% uncertainty interval [0.2, 2.7]), PDMCI: 2.4 µm2/s [0....
BackgroundBrain structure abnormalities throughout the course of Parkinson’s disease (PD) have ye... more BackgroundBrain structure abnormalities throughout the course of Parkinson’s disease (PD) have yet to be fully elucidated. Inconsistent findings across studies may be partly due to small sample sizes and heterogeneous analysis methods. Using a multicenter approach and harmonized analysis methods, we aimed to overcome these limitations and shed light on disease stage-specific profiles of PD pathology as suggested by in vivo neuroimaging.MethodsIndividual brain MRI and clinical data from 2,367 PD patients and 1,183 healthy controls were collected from 19 sites, deriving from 20 countries. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effect linear models. Patients were grouped according to the Hoehn & Yahr (HY) disease stages and compared to age- and sex-matched controls. Within the PD sample, we investigated associations between Montreal Cognitive Assessment (MoCA) scores and brain morphology.FindingsThe main analysis showed a thin...
Frontiers in Behavioral Neuroscience, 2018
Beneficial molecular and neuroplastic changes have been demonstrated in response to environmental... more Beneficial molecular and neuroplastic changes have been demonstrated in response to environmental enrichment (EE) in laboratory animals across the lifespan. Here, we investigated whether these effects extend to C-type Natriuretic Peptide (CNP), a widely expressed neuropeptide with putative involvement in neuroprotection, neuroplasticity, anxiety, and learning and memory. We determined the CNP response in 36 young (8-9 months) and 36 aged (22-23 months) male PVGc hooded rats that were rehoused with new cage mates in either standard laboratory cages or EE for periods of 14 or 28 days. Tissues were rapidly excised from four brain regions associated with memory formation (dorsal hippocampus, retrosplenial cortex, medial prefrontal cortex, and mammillary bodies) plus the occipital cortex and hypothalamus, and immediately frozen. Radioimmunoassay was used to measure bioactive CNP and the amino-terminal fragment of proCNP, NTproCNP. Because CNP but not NTproCNP is rapidly degraded at source, NTproCNP reflects CNP production whereas the ratio NTproCNP:CNP is a biomarker of CNP's local degradation rate. EE increased CNP at 14 days in all brain regions in young, but not old rats; this effect in young rats was lost at 28 days in all regions of interest. NTproCNP:CNP ratio, but not NTproCNP, was reduced in all regions by EE at 14 days in young rats, but not in old rats, which suggests a period of reduced degradation or receptor mediated clearance, rather than increased production of CNP in these young EE rats. Aged rats tended to show reduced NTproCNP:CNP ratios but this did not occur in dorsal hippocampus or mammillary bodies. This is the first study demonstrating modulation of CNP protein concentrations, and the effect of age, in response to environmental stimulation. Furthermore, it is the first to show that changes in degradation rate in vivo may be an important component in determining CNP bioactivity in neural tissues.
The Lancet Neurology, 2019
Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope... more Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation.
IntroductionBi-allelic mutations in the gene for glucocerebrosidase (GBA) cause Gaucher disease, ... more IntroductionBi-allelic mutations in the gene for glucocerebrosidase (GBA) cause Gaucher disease, an autosomal recessive lysosomal storage disorder. Gaucher disease causing GBA mutations in the heterozygous state are also high risk factors for Parkinson’s disease (PD). GBA analysis is challenging due to a related pseudogene and structural variations (SVs) that can occur at this locus. We have applied and refined a recently developed nanopore DNA sequencing method to analyze GBA variants in a clinically assessed New Zealand longitudinal cohort of PD.MethodWe examined amplicons encompassing the coding region of GBA (8.9kb) from 229 PD cases and 50 healthy controls using the GridION nanopore sequencing platform, and Sanger validation.ResultsWe detected 23 variants in 21 PD cases (9.2% of patients). We detected modest PD risk variant p.N409S (rs76763715) in one case, p.E365K (rs2230288) in 12 cases, and p.T408M (rs75548401) in seven cases, one of whom also had p.E365K. We additionally de...
The cerebral cortex underlies our complex cognitive capabilities, yet we know little about the sp... more The cerebral cortex underlies our complex cognitive capabilities, yet we know little about the specific genetic loci influencing human cortical structure. To identify genetic variants, including structural variants, impacting cortical structure, we conducted a genome-wide association meta-analysis of brain MRI data from 51,662 individuals. We analysed the surface area and average thickness of the whole cortex and 34 regions with known functional specialisations. We identified 255 nominally significant loci (P≤ 5 × 10−8); 199 survived multiple testing correction (P≤ 8.3 × 10−10; 187 surface area; 12 thickness). We found significant enrichment for loci influencing total surface area within regulatory elements active during prenatal cortical development, supporting the radial unit hypothesis. Loci impacting regional surface area cluster near genes in Wnt signalling pathways, known to influence progenitor expansion and areal identity. Variation in cortical structure is genetically corre...
Frontiers in Neurology, 2019
The extent to which Alzheimer neuropathology, particularly the accumulation of misfolded beta-amy... more The extent to which Alzheimer neuropathology, particularly the accumulation of misfolded beta-amyloid, contributes to cognitive decline and dementia in Parkinson's disease (PD) is unresolved. Here, we used Florbetaben PET imaging to test for any association between cerebral amyloid deposition and cognitive impairment in PD, in a sample enriched for cases with mild cognitive impairment. This cross-sectional study used Movement Disorders Society level II criteria to classify 115 participants with PD as having normal cognition (PDN, n = 23), mild cognitive impairment (PD-MCI, n = 76), or dementia (PDD, n = 16). We acquired 18F-Florbetaben (FBB) amyloid PET and structural MRI. Amyloid deposition was assessed between the three cognitive groups, and also across the whole sample using continuous measures of both global cognitive status and average performance in memory domain tests. Outcomes were cortical FBB uptake, expressed in centiloids and as standardized uptake value ratios (SUVR) using the Centiloid Project whole cerebellum region as a reference, and regional SUVR measurements. FBB binding was higher in PDD, but this difference did not survive adjustment for the older age of the PDD group. We established a suitable centiloid cutoff for amyloid positivity in Parkinson's disease (31.3), but there was no association of FBB binding with global cognitive or memory scores. The failure to find an association between PET amyloid deposition and cognitive impairment in a moderately large sample, particularly given that it was enriched with PD-MCI patients at risk of dementia, suggests that amyloid pathology is not the primary driver of cognitive impairment and dementia in most patients with PD.
npj Parkinson's Disease, 2019
Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and ... more Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intol...
Uploads
Papers by John Dalrymple-alford